The prior art has described several compounds that are capable of regulating the cell cycle by virtue of inhibiting cyclin dependent kinases. These compounds include butyrolactone, flavopiridol and 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine (olomoucin). Olomucin and related compounds have been shown to be inhibitors of cdc2. cdc2 (also known as cdk1) is a catalytic subunit of a family of cyclin dependent kinases that are involved in cell cycle regulation.
These cyclin dependent kinases comprise at least two subunits, namely a catalytic (of which cdc2 is the prototype) and a regulatory (cyclin). The cdk""s are regulated by transitory association with a member of the cyclin family: cyclin A (cdc2, cdk2), cyclin B1-B3 (cdc2), cyclin C (cdk8), cycline D1-D3 (cdk2-cdk4-cdk5-ckd6), cyclin E (cdk2), cyclin H (cdk7).
Each of these complexes is involved in a phase of the cellular cycle. cdk activity is regulated by post-translatory modification, by transitory associations with other proteins, and by modifications of their intracellular localization. The cdk regulators comprise activators (cyclins, cdk7/cyclin H, cdc25 phosphateses), the p9CKS and p15cdk-BP sub-units, and the inhibiting proteins (p16INK4A, p15INK4B, p21CiP1, p18, p27KiP1).
There is now considerable support in the literature for the hypothesis that cdk""s and their regulatory proteins play a significant role in the development of human tumors. Thus, in numerous tumors a temporal abnormal expression of cyclin-dependent kinases, and a major deregulation of protein inhibitors (mutations, deletions) has been observed.
The invention relates, in part, to the therapeutic uses of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine (bohemine) or other one and pharmaceutically acceptable salts thereof.
The present invention pertains to a method of treating a patient suffering from leukemia comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine (bohemine) or a pharmaceutically acceptable salt thereof.
A further aspect of the present invention relates to a method of treating a patient suffering from cancer comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine (bohemine) or a pharmaceutically acceptable salt thereof.
In a further embodiment the present invention relates to a method of treating a cancerous or leukemic proliferative disease comprising inhibiting the cdk4 and/or cdk7 enzymes by the administration of a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine (bohemine) or 2-[(1-ethyl-2-hydroxyethyl)amino]-6-benzylamino-9-isopropylpurine (roscovotine) or pharmaceutically acceptable salt thereof.
In an additional embodiment the present invention relates to a method of inducing cell death in proliferative cells comprising administering a therapeutically effective amount of the compound 2-([(3-hydroxypropyl)amino]-6-benzylamino)-9-isopropylpurine (bohemine) or 2-[(1-ethyl-2-hydroxyethyl)amino]-6-benzylamino-9-isopropylpurine (roscovotine) or pharmaceutically acceptable salt thereof.